The C-X-C motif chemokine 12 (CXCL12), also known as stromal cell-derived factor 1 (SDF-1), is a CXC chemokine protein that in humans is encoded by the CXCL12 gene. It is known to bind to two G-protein-coupled receptors, CXCR4 and CXCR7. It participates in many developmental and physiologic processes, including haematopoiesis and angiogenesis. CXCL12 plays a role in angiogenesis by recruiting endothelial progenitor cells (EPCs) from the bone marrow through a CXCR4 dependent mechanism, making it a significant factor in carcinogenesis and neovascularisation linked to tumour progression. Migration another important way in which CXCL12 influences tumour development and progression. CXCL12 also has a role in organ-specific metastasis of several cancers, where cancer cells that express the receptor CXCR4 are attracted to metastasis target tissues that release the ligand, CXCL12. CXCL12 also acts to recruit CXCR4-positive stromal cells and regulates immune cell infiltration. For example, CXCL12 may aid the formation of pre-metastatic niches through the recruitment of regulatory T cells, producing an immunosuppressive environment (Zhao et al, Oncoimmunology, 1(2): 152-161, 2012). In prostate cancer, cancer associated fibroblasts (CAFs) engage monocyte recruitment and M2 polarization through CXCL12 (Comito et al, Oncogene, 33: 2423-2431, 2014). High levels of CXCL12 are associated with low numbers of T cells in a pancreatic cancer model and it was possible to increase T cell infiltration through combined treatment with PD-L1 and CXCR4 inhibitors. This increase in T cell infiltration was accompanied by a significant reduction in tumour volume, highlighting the role of the CXCL12/CXCR4 axis in immune control of cancer (Feig et al, PNAS, 110(50): p20212-20217, 2013).
The CXCL12/CXCR4/CXCR7 pathway has therefore generated considerable interest as a potential therapeutic target given its role in tumour growth, survival and angiogenesis (Balkwill et al., Seminars in Cancer Biology, 14: 171-179, 2004).
WO 2008/018641 (Ono Pharmaceutical Co. Ltd and Medarex, Inc.) discloses human monoclonal antibodies that specifically bind to SDF-1 and proposes their medical uses for treating various B cell malignancies, including breast cancer, multiple myeloma and non-Hodgkin's lymphoma and autoimmune disorders. Zhong et al. (Clinical Cancer Research, 19: 4433-4445, 2013; DOI: 10.1158/1078-0432.CCR-13-0943) discloses a humanised version of a hamster monoclonal antibody 30D8 and shows that it was capable of binding to human and murine CXCL12 in in vitro assays.